Among brain tumors, many tumors originating from meninges, brain or spinal nerve, such as meningiomas and schwannomas, are benign brain tumors and can be completely cured if they can be removed by surgery. In contrast, neuroepithelial tumors including glioma are basically malignant brain tumors. Especially, grade 4 glioblastoma shows extremely poor prognosis (5-year survival rate is about 10%) even if radiation therapy and chemotherapy are performed after removal by craniotomy. A major reason for the lack of effective chemotherapy for brain tumor is the presence of a blood-brain barrier. On the other hand, temozolomide, which is a new drug effective for glioblastoma, was approved in Japan in 2006. This drug has a very small molecular weight (194 Da) and was clarified to be able to cross the blood-brain barrier by diffusion. However, the drug has only been able to extend life expectancy from 12 months to 16 months. To dramatically improve the treatment results for malignant brain tumor in the future, therefore, it is essential to develop a therapeutic drug that accumulates in the brain tumor at an overwhelmingly high concentration and can actively cross the wall of vascular endothelium, rather than a passive method relying on the diffusion of small molecules as for the blood-brain barrier.
Recently, the economic burden on patients is becoming increasingly heavy due to the rising research and development expenses and the widespread use of antibody pharmaceuticals. In the future, this trend is considered to be further accelerated by the sophistication of medical care such as diagnosis system by genetic information and the like. In addition, the impact of these soaring drug prices on national health care costs is also immeasurable. Furthermore, expensive antibody pharmaceuticals become inaccessible to underdeveloped countries, leading to further medical inequality on a global scale. If measures are to be taken for the above-mentioned problems from a longer-term perspective, it is necessary to explore the possibility of inexpensive biopharmaceuticals such as short-chain peptides in the future in addition to the pursuit of a superior drug seed.
Fukuda, one of the present inventors, hosted a laboratory in Sanford Burnham Prebys Medical Discovery Institute in the United States for more than 30 years until she was assigned to the National Institute of Advanced Industrial Science and Technology in 2014. During that time, Fukuda succeeded for the first time in the world in inhibiting sugar chain-dependent cancer metastasis by using a peptide mimicking the structure of sugar chain (non-patent document 1). Furthermore, in the process of examining vascular endothelial receptors interacting with these sugar chain mimetic peptides, she found that a peptide named IF7 binds to annexin A1 (Anxa1) (non-patent document 2). Anxa1 was clarified by the group of Jan Schnitzer et al. to be the most specific of the currently known tumor vessel specific marker molecules and is expressed intracellularly in normal cells but strongly expressed on luminal surfaces adjacent to the bloodstream in tumor neovascular endothelial cells (non-patent document 3). Fukuda et al. clarified that a drug (IF7-SN38) obtained by binding an anticancer agent (SN38) to IF7 clears tumor in cancer-bearing mice at a low dose (non-patent document 2). While IF7 binds to the N-terminal region of mouse Anxa1, the amino acid sequence in that region is highly conserved between mouse and human. Therefore, IF7-SN38 may also be useful in human. This finding was taken up in the “In this issue in PNAS” of the PNAS journal and the NIH introduced a special article. The finding further attracted considerable attention, including reports by media around the world.